The chemical formation of closed-ring organic molecules has posed many issues for structural organic chemists. This has been particularly true with regard to synthetic reactions involving sugars and polyols, the acid dehydration of which leads to inernal anhydro compounds (mono- and dianhydro products). Fleche and Huchette, Staerk, 38 (1985) 26-30.
The earliest work in this area was done on 1,4:3,6-dianhydro-D-mannitol by Fauconnier in 1884. Only sporadic work followed until the 1940's and 1950's, when intensive work was done on all possible isomers of 1,4:3,6-dianhydrohexitols. Stoss and Hemmer, Adv. Carbohydrate Chem. and Biochem. (1991) 93-173. Since then a large body of chemical literature has developed in this area.
The 1,5:3,6-dianhydrohexitols belong to the so-called “biomass-derived substances”, obtainable from natural products. Therefore, these compounds are classified as “regenerable resources.” Furthermore, 1,4:3,6-dianhydrohexitols, such as isosorbide, can be used as starting materials and intermediates in various organic synthetic reaction schemes. For example, isosorbide is useful in the formation of numerous pharmaceutical compounds, in food production, cosmetic production, plastic and polymer production, and in other industrial uses such as in the production of polyurethane, polycarbonate, polyesters, and polyamides. Stoss and Hemmer, 1991.
Of the known isohexides, isosorbide is considered to be that of the highest importance. Stoss and Hemmer (1991) describe the putative steps leading from D-glucitol (also referred to in the art as sorbitol) to isosorbide. Acidic media are generally used for dehydrating the sugar alcohol substrate. Especially to enhance the yield and to avoid side reactions, certain modifications of the reaction conditions have been employed over the years, with various impacts on yield of isosorbide product. Stoss and Hemmer, 1991.
Several processes for the production of anhydrosugar alcohols (including isohexides such as isosorbide) are known. See, for example, PCT application number PCT/US99/00537 (WO 00/14081), collecting methods and disclosing a continuous production method with recycling of organic solvent. Most methods involve the use of concentrated acids and organic solvents. Goodwin et al. (Carbohydrate Res. 79 (1980), 133-141) have disclosed a method involving the use of acidic-cation-exchange resin in place of concentrated, corrosive acids, but with low yield of isosorbide product. An alternative, supersaturation-based method is disclosed in U.S. Pat. No. 4,564,692 (Feldmann et al., Jan. 14, 1986). However, a need continues in the art for a process for production of very pure isosorbide, at reasonable yields, and preferably without the use of potentially hazardous organic solvents.